Ionotropic glutamate receptors are the main mediators of excitatory synaptic signals in the mammalian central nervous system. Glutamate binding to this receptor triggers the formation of transmembrane ion channels in the protein, permitting cations to flow down their electrochemical gradients across the postsynaptic membrane, depolarizing it and thereby stimulating the receiving cell. Excess glutamate, on the other hand, over activates the ionotropic glutamate receptors triggering a cascade of events resulting in neuronal death. This excitotoxic pathway is thought to be a major factor in neurodegeneration associated with a variety of acute and chronic disorders such as stroke, ALS, and Alzheimer's disease, and therefore antagonists of the ionotropic glutamate receptors have been identified as good candidates for the treatment of these diseases. A large body of initial work focused on the antagonists of the NMDA subtype of the glutamate receptors since these are Ca 2+ permeable. However, more recently it has become apparent that Ca 2+ permeable subtype of AMPA receptors may indeed be one of the primary mediators of neuronal death. For instance, selective death of motor neurons observed in ALS is thought to be mediated by the activation of the high density of Ca 2+ permeable AMPA receptors in motor neurons. The antagonists currently available for the AMPA receptors, however, are not as effective in the treatment of these diseases mainly due to their insolubility. There is hence an ongoing search for soluble antagonists of the AMPA receptor, which would be greatly facilitated by a high throughput screening assay that would be able to identify antagonists of this receptor. Traditionally, radioactive ligand binding assays have been used to screen for drugs that bind to this important protein. However, the drugs identified have to then be characterized by patch clamp methods to determine if they exhibit antagonistic properties, which is extremely labor intensive and low throughput. Here we propose to develop a fluorescence based high throughput assay that will not only allow for the screening of drugs that bind to the receptor with high specificity, but will also provide a direct readout of the functional consequences (activation or inhibition) of the drug binding, thus allowing for a selective screening of drugs with the desired functional properties.